Poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) is a nuclear enzyme in most eukaryocytes and the main function thereof is to synthesize poly(ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD+) as its substrate and transfer the synthesized poly(ADP-ribose) to receptor protein, thereby regulating the function of protein (see: Schreiber, V.; Dantzer, F.; Ame, J. C.; de Murcia, G. Poly(ADPribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 2006, 7, 517-528). At least 16 homologs in PARP family have been found and only six members (PARP1, PARP2, PARP3, PARP4 (VPARP), Tankyrase1 and Tankyrase2, respectively) have poly(ADP-ribose) polymerase function according to stringent structural and functional criteria, while other members in the family may function as mono-ADP-ribosyltransferases (see: Rouleau, M.; Patel, A.; Hendzel, M. J.; Kaufmann, S. H.; Poirier, G. G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 2010, 10, 293-301). Only PARP1 and PARP2 in PARP family can be activated by the breaks of DNA strands, mediate polyADP-ribosylation, and participate in the repair of DNA single-strand breaks through the base-excision repair (BER) pathway. PolyADP-ribosylation causes chromatin depolymerization in the injured site, initiates repair mechanism and accelerates the repair of DNA damage. In that respect, PARP1 and PARP2 play dual roles including detection of DNA damage and signaling transduction during the repairing process. Human PARP1 is a polypeptide with molecular weight of 113 kDa and contains three functional domains. The DNA binding domain (DBD) located at the N-terminal end contains two Zinc fingers recognizing DNA single-strand breaks and double-strand breaks. The automodification domain is located in the middle region, by which PARP1 binds to ADP ribosyl thereby polyADP-ribosylating PARP itself. And the catalytic domain located in the C-terminal end acts as the basis for transferring NAD+ to ADP ribose and is the active structure for the function of PARP1. In contrast, human PARP2 is a polypeptide with molecular weight of 62 kDa. Its DNA binding domain is different from that of PARP1, and accordingly the main function thereof is to recognize the gap due to the deletion of nucleotide in the damaged DNA strand. The catalytic domain located at the C-terminal end of PARP2 is similar to that of PARP1, however, the fine difference in their structures still reflects the difference in their target proteins to be catalyzed. PARP1 and PARP2 play an important role in the repair of DNA damage, genome stability and regulation of cell apoptosis through base excision repair. Therefore, they become one of the most interesting targets in anti-tumour drug research in recent years (see: Yelamos, J.; Farres, Jordi.; Llacuna, L.; Ampurdanes, C.; targeCaballero, J. M. PARP-1 and PARP-2: New players in tumour development. Am. J. Cancer Res. 2011, 1(3), 328-346). Moreover, the important role of PARP in the process such as inflammation, ischemia reperfusion, etc., indicates that PARP also has potential application value in the diseases (such as diabetes, cardiovascular disease, etc.) except for malignant tumours (see: Peralta-Leal, A.; Rodriguez-Vargas, J. M.; Aguilar-Quesada, R.; Rodriguez, M. I.; Linares, J. L.; de Almodovar, M. R.; Oliver, F. J. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radical Biol. Med. 2009, 47, 13-26).
In 2005, it was reported in Nature that PARP1/2 inhibitors used alone have a significantly intibiting effect on breast cancer cells with defective BRCA1/2 (see: Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913-917. And Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N.; Johnson, D. A.; Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C.; Martin, N. M.; Jackson, S. P.; Smith, G. C.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434, 917-921.), which represented a breakthrough in the research of using PARP1/2 inhibitors alone for anti-tumour treatment. DNA is unstable and can be damaged due to the exposure to harsh environment (such as ultraviolet radiation, ionizing radiation, etc.), byproducts from normal cell metabolism, and breaks in some DNA chemical bonds. For keeping the genome intact and stable, normal human cells need to repair DNA damages caused by various factors for tens of thousands of times every day. Major DNA repair pathways include base excision repair (BER), nucleotide-excision repair (NER), homologous recombination (FIR) and nonhomologous end joining (NHEJ); wherein, BER in which PARP1/2 participates is the uppermost repair pathway for DNA single-strand breaks, while FIR is the uppermost repair pathway for DNA double-strand breaks (see: Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 2001, 411, 366-74). BRCA1/2 are famous tumour-suppressor genes and key repair factors in HR. Defects in BRCA1/2 will increase the unstability of genome and cause the occurrence of malignant tumour. For such cells, DNA double-strand breaks can not be repaired by HR and breaks will finally lead to the death of cells. Inhibiting PARP1/2 in BRCA1/2-deficient tumor cells leads to increase the accumulation of DNA single-strand breaks; when colliding with the replication forks in progression, DNA single-strand breaks are converted to lethal double-strand breaks which ultimately results in cell killing. The phenomenon that inhibition of PARP1/2 together with defects of BRCA1/2 kills cells is so called as synthetic lethality. The use of the synthetic lethality phenomenon provides a new strategy for treating malignant tumours, thereby opening a new era of PARP1/2 inhibitors for research and development of high selectivity anti-tumour drugs (see: Kaelin, W. G., Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 2005, 5, 689-698; He J X, Yang C H, Miao Z H. PARP inhibitors as promising cancer therapeutics. Acta Pharmacol. Sin. 2010, 31, 1172-1180).
The first generation of PARP1/2 inhibitors was emerged thirty years ago, and most of them are nicotinamide analogues, but such inhibitors lack selectivity and effectiveness. The second generation of PARP1/2 inhibitors was developed in 1990s and clear structure-activity relationships were established; therefore, PARP1/2 inhibitors have more clear structure features. The structure features include an electron-rich aromatic ring; a carboxamide group at least containing one free hydrogen for forming hydrogen bonding; and one non-cleavable chemical bond at the position corresponding to the 3-position pharmacophore of the carboxamide, etc. (see: Zaremba, T.; Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anti-Cancer Agents Med. Chem. 2007, 7, 515-523). At present at least seven PARP1/2 inhibitors as new anti-tumour drugs have entered clinical trials (see: C. Toulmondel, U. M.; Bonnefoi, H. A review of PARP inhibitors: from bench to bedside. Annals of Oncology 2011, 22(2), 268-79; Ferraris, D. V. Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic. J. Med. Chem. 2010, 53, 4561-4584; He J X, Yang C H, Miao Z H. PARP inhibitors as promising cancer therapeutics. Acta Pharmacol. Sin. 2010, 31, 1172-1180). However, these inhibitors still have many disadvantages, such as relatively low oral bioavailability, lack of selectivity for PARP subtypes except PARP1/2 and so on.
As well known, 2-arylbenzofuran compounds widely exist in natural products. Due to their good bioactivities and potential pharmaceutical values, the researchers always pay a close attention to them. On the one hand, the scientists studying natural products continuously extract and isolate novel 2-arylbenzofuran compounds from natural products, and investigate and develop biological activities thereof (see: Halabalaki, M.; Aligiannis, N.; Papoutsi, Z.; Mitakou, S.; Moutsatsou, P.; Sekeris, C.; Skaltsounis, A.-L. Three New Arylobenzofurans from Onobrychis ebenoides and Evaluation of Their Binding Affinity for the Estrogen Receptor. J. Nat. Prod. 2000, 63, 1672-1674; and Tsai, I. L.; Hsieh, C.-F.; Duh, C.-Y. Additional Cytotoxic Neoligants From Perseaobovatifolia. Phytochemistry 1998, 48, 1371-1375); on the other hand, great efforts have been made by the chemists to develop and optimize a series of methods for constructing 2-arylbenzofuran compounds (see: Ziegert, R. E.; Torang, J. Knepper, K.; Brase, S. The Recent Impact of Solid-Phase Synthesis on Medicinally Relevant Benzoannelated Oxygen Heterocycles. J. Comb. Chem. 2005, 7, 147-169. Chen, C. Y.; Dormer, P. G. Synthesis of Benzo[b]furans via CuI-Catalyzed Ring Closure. J. Org. Chem. 2005, 70, 6964-6967. And Liang, Z. D.; Hou, W. Z.; Du, Y. F.; Zhang, Y. L.; Pan, Y.; Mao, D.; Zhao, K. Oxidative Aromatic C—O Bond Formation: Synthesis of 3-Functionalized Benzo[b]furans by FeCl3-Mediated Ring Closure of α-Aryl Ketones. Org. Lett. 2009, 21, 4978-4981, etc.). Various activities have been exhibited by reported 2-arylbenzofuran compounds, such as retinoic acid receptor (RAP) agonists (see: Santin, E. P.; Khanwalkar H.; Voegel, J.; Collette, P.; Mauvais, P.; Gronemeyer, H.; A. R. de Lera. Highly Potent Naphthofuran-Based Retinoic Acid Receptor Agonists. ChemMedChem. 2009, 4, 780-791), tubulin polymerization inhibitors (see: Flynn, B. L.; Hamel E.; Jung, M. K. One-Pot Synthesis of Benzo[b]furan and Indole Inhibitors of Tubulin Polymerization. J. Med. Chem. 2002, 45, 2670-2673), metalloproteinase inhibitors (see: Nakatani, S.; Ikura, M.; Yamamoto, S.; Nishita, Y.; Itadani, S.; Habashita, H.; Sugiura, T.; Ogawa, K.; Ohno, H.; Takahashi, K.; Nakai, H.; Toda, M. Design and synthesis of novel metalloproteinase inhibitors. Bioorg. Med. Chem. 2006, 14, 5402-5422), and antimicrobial agents (see: Emirdag-Ozturk, S.; Karayildirim, T.; Anil, H. Synthesis of egonol derivatives and their antimicrobial activities. Bioorg. Med. Chem. 2011, 18, 1179-1188). Due to the good biological activities and potentially huge medical values, some compounds have been patented, for example, a use for treating diseases relating to prostaglandin E2 receptor (WO 2008/098978), a use for treating diseases relating to cannabinoid receptor (WO 2011/022679), a use for treating diseases relating to estrogen receptor (WO 2009/124968), a use for preventing bacterial and fungal infection (WO 2005/047275), and a use for treating bladder muscle reflex contraction disease (EP 0306226A2). The above reported 2-arylbenzofuran compounds were not covered for the use as PARP1/2 inhibitors thereof according to the present invention.
Based on above reasons, the inventors designed and synthesized novel 2-arylbenzofuran-7-carboxamide compounds as PARP1/2 inhititors with high selectivity. The compounds according to the present invention have clear structure-activity relationships, and some compounds such as compound 5b have high selectivity to PARP1/2 and excellent bioavailability (After 10 mg/kg of 5b was administrated to rats by gavage, the absolute bioavailability was 58.9%, while the oral bioavailability of rats for the compound AZD2281 during phase II clinical trials was only 11.1%). Such a novel PARP1/2 inhibitor is of promise to become a novel anti-tumour medicament.